Hepatitis C Drug Pipeline

Category Archives: Genotype 4

Four studies of AbbVie’s two drug combination—glecaprevir (protease inhibitor) and pibrentasvir (NS5A inhibitor) were presented.

Endurance 1:703 genotype 1 non-cirrhotic treatment naïve and treatment experience patients. The patients were treated for 8 or 12 weeks. No ribavirin was used in the study. The cure rates were 99% to 100% across all treatment groups. Endurance 2: 199 genotype 2 non-cirrhotic treatment-naïve and treatment-experience patients treated for 12 weeks achieved 99% to 100%.

Surveyor-II Part 3 Phase 2/3: In genotype 3 patients who were cirrhotic and treatment experienced but who had not been previously treated with a NS5A inhibitor were treated with glecaprevir plus pibrentasvir. Those treated for 12 weeks achieved 91% to 98% cure rates and those treated for 16 weeks achieved 96% cure rates. This treatment was particularly effective for people with end-stage kidney disease.

Surveyor-II Part 4: In genotype 2, 4, 5 or 6 patients without cirrhosis. There were a total of 203 patients—both treatment naïve and treatment experienced (no NS5A treatment experienced). The treatment period was 8 weeks. The cure rates were 98% for genotype 2; 93% for genotype 4; 100% for genotype 5 and 90% for genotype 6—although the number of patients in the genotype 5 and 6 groups were very small.

Expedition-IV: The goal of the study was to treat patients with renal impairment. There were 104 genotype 1 through 6 patients enrolled. The majority of the patients had severe renal impairment, and 82% were on dialysis (filtering of the blood because the kidneys are impaired). The patients were treatment naïve and treatment experienced (no NS5A experienced). The cure rate was 99% (103 of 104)—one patient discontinued treatment before the trial ended.

AbbVie has submitted their study results to the Food and Drug Administration forapproval inDecember.

Alan Franciscus is the Executive Director of the Hepatitis C Support Project and Editor-in-Chief of the HCV Advocate.

In the POLARIS-1 and POLARIS-4 studies, 445 patients with genotype 1-6 HCV infection who were previously treated with direct-acting antiviral agents (DAAs) received 12 weeks of SOF/VEL/VOX. The POLARIS-1 study enrolled patients who failed prior treatment with an NS5A inhibitor. The POLARIS-4 study enrolled patients who failed prior treatment with a DAA that was not an NS5A inhibitor, most with either an NS5B inhibitor alone (73 percent) or an NS5B inhibitor and an NS3/4A protease inhibitor (25 percent).

In the POLARIS-2 and POLARIS-3 studies, 611 patients who were not previously treated with a DAA received 8 weeks of SOF/VEL/VOX. The POLARIS-2 study enrolled patients with genotype 1-6 HCV infection with or without compensated cirrhosis. The POLARIS-3 study enrolled patients with genotype 3 HCV infection, all of whom had compensated cirrhosis.

The primary endpoint for all studies was SVR12. The intent-to-treat SVR12 rates observed in the POLARIS studies are summarized in the following table. Complete results from all four studies will be presented at The Liver Meeting® 2016 in Boston.

Study

Population

Genotype

Treatment

Duration

SVR12 Rates

POLARIS-1

NS5A inhibitor-experienced

41 percent (172/415) had cirrhosis

1, 2, 3, 4, 5, 6

SOF/VEL/VOX

12 Weeks

96%

(253/263)

Placebo

12 Weeks

0%

(0/152)

POLARIS-4

DAA-experienced (No NS5A inhibitor)

46 percent (153/333) had cirrhosis

1, 2, 3, 4

SOF/VEL/VOX

12 Weeks

97%

(177/182)

SOF/VEL

12 Weeks

90%

(136/151)

POLARIS-2

DAA-naïve

18 percent (174/941) had cirrhosis

1, 2, 3, 4, 5, 6

SOF/VEL/VOX

8 Weeks

95%

(476/501)

SOF/VEL

12 Weeks

98%

(432/440)

POLARIS-3

DAA-naïve

All had cirrhosis

3

SOF/VEL/VOX

8 Weeks

96%

(106/110)

SOF/VEL

12 Weeks

96%

(105/109)

Patients treated with SOF/VEL/VOX for 12 or eight weeks had similar overall incidence of adverse events compared to placebo-treated or SOF/VEL-treated patients. The most common adverse events among patients who received SOF/VEL/VOX were headache, fatigue, diarrhea and nausea. Among the 1,056 patients who received SOF/VEL/VOX in the four studies, one patient (less than one percent) receiving SOF/VEL/VOX for 12 weeks discontinued due to an adverse event.

“Despite recent advances that have provided high cure rates and simplified treatment for most HCV patients, those who have failed previous treatment with direct acting antivirals continue to represent an unmet medical need. The POLARIS study results demonstrate that combining three potent antivirals with different mechanisms of action and high barriers to resistance can provide high cure rates for patients who have failed other highly effective oral DAA regimens,” said Norbert Bischofberger, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. “Based on these Phase 3 results, we plan to submit regulatory applications for SOF/VEL/VOX for the treatment of chronic HCV in the United States in the fourth quarter of 2016 and shortly thereafter in Europe.”

About the POLARIS Studies

The POLARIS-1 study was a double-blind, placebo-controlled study in 415 genotype 1-6 NS5A inhibitor-experienced patients. The most common prior NS5A inhibitors were ledipasvir (55 percent) and daclatasvir (23 percent).

The open-label POLARIS-4 study evaluated the use of SOF/VEL/VOX or SOF/VEL for 12 weeks in 333 genotype 1-4 HCV-infected patients with prior DAA experience that did not include an NS5A inhibitor. Most patients (85 percent) had prior DAA experience with sofosbuvir.

The open-label POLARIS-2 study evaluated the use of SOF/VEL/VOX for eight weeks or SOF/VEL for 12 weeks in 941 genotype 1-6 DAA-naïve HCV-infected patients, including 18 percent with cirrhosis and 23 percent who had previously failed treatment with an interferon-based regimen.

The open-label POLARIS-3 study randomized patients with genotype 3 HCV infection and cirrhosis to receive SOF/VEL/VOX daily for eight weeks or SOF/VEL for 12 weeks. Of the 219 patients treated, 31 percent had previously failed treatment with an interferon-based regimen.

The POLARIS-1, POLARIS-3 and POLARIS-4 studies met their respective pre-specified primary endpoints for the patients receiving SOF/VEL/VOX. The POLARIS-2 study did not meet its primary endpoint; with a pre-specified 5 percent margin, the SVR12 rate for patients receiving treatment with SOF/VEL/VOX for eight weeks was not statistically non-inferior to the SVR12 rate for patients receiving SOF/VEL for 12 weeks.

About SOF/VEL/VOX

The SOF/VEL/VOX fixed-dose combination is an investigational product and its safety and efficacy have not been established. It has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of chronic genotype 1 HCV patients who have previously failed an NS5A inhibitor-containing regimen.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.

On June 28, 2016, Epclusa (ep-Kloo-suh)—a combination of two drugs—sofosbuvir, a polymerase inhibitor, and velpatasvir, an NS5A inhibitor, was approved by the Food and Drug Administration (FDA) to treat adults infected with chronic hepatitis C (HCV) genotype 1, 2, 3, 4, 5 and 6. It is taken with and without ribavirin. It is combined into one pill taken once-a-day. It can be taken with and without food. Epclusa is manufactured by Gilead Sciences INC. The treatment duration is 12 weeks.

First-in-Class

All genotypes – Epclusa is the first HCV medication that can successfully treat all six genotypes.

No ribavirin for most people – the cure rates are from 97% to 100% in those without cirrhosis or with compensated cirrhosis. Ribavirin is still needed for those with decompensated cirrhosis, but the treatment duration is the same and the cure rates are 85% to 100%.

Genotype testing – Epclusa cures all HCV genotypes at very high rates and for the same duration. This eliminates the need for expensive genotype testing.

High cure rates for genotype 3 – The clinical trials of people without cirrhosis or compensated cirrhosis achieved cure rates of 95%. In people with decompensated cirrhosis the addition of ribavirin to Epclusa produced 85% cure rates. Previous therapies produced suboptimal cure rates and treatment duration was 24 weeks especially for people with cirrhosis.

Genotype 2 – in clinical trials of Epclusa (without ribavirin) people without cirrhosis or with compensated cirrhosis the cure rate was 100%. In people with decompensated cirrhosis the addition of ribavirin increased the cure rate to 100%. Previously, treatment for all genotype 2 patients included ribavirin for everyone with genotype 2 and the cure rates were not as high.

Lower cost – The wholesale acquisition cost (WAC) for Epclusa is $74,760.00 for a 12-week course of treatment. It is too soon to tell if insurance companies, Medicaid and Medicare will cover it since it was just approved, but since it is lower than the price of Sovaldi and Harvoni there may be more of a chance of coverage when the prices are negotiated.

Side Effects: The most common side effects of Epclusa that occurred in more than 10% of patients in the clinical trials were headache and fatigue.

Pregnancy: There are no studies of Epclusa in pregnant women. Ribavirin can cause birth defects and miscarriages. If you are a male taking ribavirin, you and your female sexual partner must use two types of effective birth control. Your female sexual partner will have to take a pregnancy test before and during treatment and 6 months after treatment ends. If you are a female taking ribavirin, you and your male sexual partner must use two types of effective birth control. Additionally, women have to take a pregnancy test before, during and 6 months after treatment ends.

Listed below are the cure rates for genotypes 1, 2, 3, 4, 5 and 6.

The results below included patients who were treatment naive and treatment experienced

Epclusa for 12 weeks – no ribavirin in patients without cirrhosis or with compensated cirrhosis

Note: at the beginning of the article I wrote that Epclusa could treat all genotypes. You might have wondered why I didn’t include information about genotype 7. Genotype 7 was discovered a few years ago and only a handful of people have been identified. Come to find out in the clinical trials of Epclusa one patient who was enrolled in Gilead’s Astral 1 trial who was incorrectly identified as gentype 2, but was later retested as genotype 7. The patient was treated with Epclusa for 12 weeks and was cured. So Epclusa does cure all genotypes.

Check out our newHCV Medication Blogfor information about all of the direct-acting antiviral medications approved by the Food and Drug Administration (FDA) to treat chronic hepatitis C.

Gilead presented data on GS-9857 (protease inhibitor) combined with sofosbuvir (polymerase inhibitor) and velpatasvir (NS5A inhibitor) to treat genotype 1 through 6 with and without cirrhosis. The information presented is from their phase 2 clinical studies.* In the group of treatment naïve patients treated for 6 weeks the cure rate was 79% (53 of 67 pts); the treatment naïve group that was treated for 8 weeks the cure rate was 96% (95 of 99 pts)

In another study presented with the same combination to treat treatment-experienced genotype 1 through 6 and who had been treated with a previous course treatment—prior NS5A experienced (27%); non-NS5A experience (52%), direct-acting antiviral experienced (DAA (52%)), and 21% that failed an interferon-based therapy without a DAA. The cure rate was 99% (127 of 128 pts).

In yet another study GS-9857 with sofosbuvir/velpatasvir was tested to treat DAA experienced genotype 1 patients with cirrhosis. The treatment period was 12 weeks. The cure rate was 100% (24 of 24 pts).

The most common side effects were headache, fatigue, diarrhea and nausea.

The fixed dose combination of sofosbuvir, velpatasvir and GS-9857 is currently in 4 phase 3 clinical trials (POLARIS 1, 2, 3 and 4). The Food and Drug Administration has granted the combination as Breakthrough Therapy for those who have previously failed an NS5A inhibitor-containing regimen.

Editorial Comments

The Gilead studies produced excellent results and show great promise. The need for treatment of people who are cirrhotic, have failed prior therapy, or have developed RAVs are some of the most important obstacles left in the treatment landscape. That is unless you count access to HCV medications.

*I did not include the results of the arms that included ribavirin because the cure rates were similar between the arms that included ribavirin and the arms that did not include ribavirin.

“These results move us closer to our ultimate goal of providing a treatment option for as many hepatitis C patients as possible. We will continue to examine our investigational, pan-genotypic regimen through our dedicated clinical trial program, including an eight-week duration across all genotypes,” saidRob Scott, M.D., vice president, development and chief medical officer, AbbVie.

In separate late-breaking data from the SURVEYOR-2 study, 100 percent of GT3 chronic HCV infected patients with compensated cirrhosis (Child-Pugh A) new to therapy achieved SVR12with 12 weeks of treatment both with and without RBV (n=24/24 in each arm).3No patients discontinued treatment due to adverse events.3Data in GT3 chronic HCV infected patients with and without cirrhosis were featured in the official ILC 2016 press program.

“The recent evolution in hepatitis C treatment has resulted in high cure rates for many patients with specific genotypes, but there remain distinct areas of unmet need,” saidPaul Kwo, M.D., professor of medicine at theIndiana University School of Medicine. “These new data show us the potential of ABT-493 and ABT-530 in genotype 3 patients new to therapy even with the added complication of compensated cirrhosis.”

In a pooled analysis of 531 patients across both SURVEYOR studies, of five treatment regimens of ABT-493 and ABT-530 evaluated, the most commonly reported adverse events were fatigue (18 percent), headache (17 percent), nausea (13 percent) and diarrhea (10 percent).5Three patients across all study arms evaluated to date, two of whom received RBV, discontinued study drugs early due to adverse events.5

Overview of SURVEYOR-1 and SURVEYOR-2 Clinical Data Presented at ILC:

Patient Profile/Study

Patient number (n)/

Patient Population

Duration of Treatment

Treatment Regimen

SVR12Rates

ITT*

GT1

Non-cirrhotic1

SURVEYOR-1

n=34

Treatment-naïve=85%

pegIFN/RBV treatment experienced=15%

8 weeks

ABT-493 (300mg) + ABT-530 (120mg) once daily

97%

(n=33/34)

GT2

Non-cirrhotic1

SURVEYOR-2

n=54

Treatment-naïve=87%

pegIFN/RBV treatment

experienced=13%

8 weeks

ABT-493 (300mg) + ABT-530 (120mg) once daily

98%

(n=53/54)

GT3

Non-cirrhotic2

SURVEYOR-2

n=29

Treatment-naïve =100%

8 weeks

ABT-493 (300mg) + ABT-530 (120mg) once daily

97%

(n=28/29)

GT3

Cirrhotic3

(Child-Pugh A)

SURVEYOR-2

n=24

Treatment-naïve= 100%

12 weeks

ABT-493 (300mg) + ABT-530 (120mg) without RBV

once daily

100%

(n=24/24)

n=24

Treatment-naïve=100%

12 weeks

ABT-493 (300mg) + ABT-530 (120mg) +

RBV (800mg)

once daily

100%

(n=24/24)

GT 4,5,6

Non-cirrhotic4

SURVEYOR-1

n=34

(GT4=22; GT5=1; GT6=11)

Treatment-naïve=85%

pegIFN/RBV treatment experienced=15%

12 weeks

ABT-493 (300mg) + ABT-530 (120mg) once daily

100%

(n=34/34)

*

Intent-to-treat (ITT) population is defined as all patients who received at least one dose of the study drugs

About SURVEYOR-11,4,5SURVEYOR-1 is an ongoing Phase 2 two-part study designed to evaluate the safety and efficacy of ABT-493 and ABT-530, with and without RBV, for eight to 12 weeks, in cirrhotic and non-cirrhotic adult genotype 1 patients, and non-cirrhotic adult patients with genotypes 4, 5 or 6 chronic HCV infection who were new to therapy or did not respond to previous treatment with pegylated interferon (pegIFN)/RBV (null responder).

About SURVEYOR-21,2,3,5SURVEYOR-2 is an ongoing Phase 2, four-part study designed to evaluate the safety and efficacy of ABT-493 and ABT-530, with or without RBV, in adult patients with genotypes 2, 3, 4, 5 or 6 chronic HCV infection who were new to therapy or had failed previous treatment with pegylated interferon (pegIFN)/RBV.

The primary endpoint of both studies is the percentage of subjects achieving SVR12.

Safety and efficacy data for Part 1 of the studies were presented at The Liver Meeting® 2015, the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) inSan Francisco.

About pooled safety analysis of SURVEYOR-1 and SURVEYOR-25531 patients were included in this safety analysis: 26 percent GT1, 24 percent GT2, 43 percent GT3, and 6 percent with GT4, 5 or 6 infection. Patients across genotypes received ABT-493/ABT-530 at five doses: 300/120mg (n=258), 300/120mg with RBV (n=27), 200/120mg (n=121), 200/120mg with RBV (n=56), and 200/40mg (n=69).

About AbbVie’s HCV Clinical Development ProgramAbbVie’s HCV clinical development program is intended to advance scientific knowledge and the clinical care of people with chronic HCV infection by investigating pan-genotypic (genotypes 1-6), all-oral, ribavirin-free, once-daily treatment for 12 weeks. An eight-week treatment duration with ABT-493 and ABT-530 will be investigated across all genotypes in our comprehensive Phase 2/Phase 3 clinical trial program, which focuses on areas of ongoing need in HCV.

ABT-493 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors.

About AbbVieAbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company’s mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world’s most complex and serious diseases. Together with its wholly-owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visitwww.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

1Poordad, F et al. High SVR Rates with the Combination of ABT-493 + ABT-530 for 8 Weeks in Non-Cirrhotic Patients with HCV Genotype 1 or 2 Infection. Poster presentation #SAT-157; presented at The International Liver Congress™ (ILC), the Annual Meeting of the European Association for the Study of the Liver (EASL) inBarcelona, Spain,April 13-17, 2016.2Muir, A et al. High SVR Rates with ABT-493 + ABT-530 Co-Administered for 8 Weeks in Non-Cirrhotic Patients with HCV Genotype 3 Infection. Oral presentation #PS098; presented at The International Liver Congress™ (ILC), the Annual Meeting of the European Association for the Study of the Liver (EASL) inBarcelona, Spain,April 13-17, 2016.3Kwo, P et al. 100% SVR12with ABT-493 And ABT-530 with or without Ribavirin in Treatment-Naïve HCV Genotype 3-Infected Patients with Cirrhosis; Late Breaker presentation #LB01; presented at The International Liver Congress™ (ILC), the Annual Meeting of the European Association for the Study of the Liver (EASL) inBarcelona, Spain,April 13-17, 20164 Gane, E et al. 100% SVR4and Favorable Safety of ABT-493 + ABT-530 Administered for 12 Weeks in Non-Cirrhotic Patients with Genotypes 4,5, or 6 Infection (SURVEYOR-I). Poster presentation #SAT-137; presented at The International Liver Congress™ (ILC), the Annual Meeting of the European Association for the Study of the Liver (EASL) inBarcelona, Spain,April 13-17, 2016.5Kwo, P et al. Safety of ABT-493 and ABT-530 Co-Administered in Patients with HCV Genotype 1-6 Infection: Results From the SURVEYOR-I and SURVEYOR-II Studies; Poster presentation #SAT-239; presented at The International Liver Congress™ (ILC), the Annual Meeting of the European Association for the Study of the Liver (EASL) inBarcelona, Spain,April 13-17, 2016.

SOURCE AbbVie

Contact(s)

On January 4, 2016, Gilead issued a press release to announce that the U.S. Food and Drug Administration (FDA) granted priority review to sofosbuvir (polymerase inhibitor) plus velpatasvir (a pan-genotypic NS5A inhibitor). Gilead stated that FDA approval is expected on June 28, 2016.
Below is a brief overview of study results from articles published in the New England Journal of Medicine (vol. 373 no.27 December 31, 2015).

Genotype 1, 2, 4, 5 and 6 (ASTRAL Studies)

In the group of patients with genotype 1, 2, 4, 5, and 6 (624 patients) the cure rates were 99% across all the genotypes. Less than 1% of patients discontinued treatment due to side effects. The most common side effects were headache, fatigue, sore throat, runny nose, and nausea.
Genotype 2 and 3 (ASTRAL 2 & 3 Study)

ASTRAL 2: The results from the Phase 3 clinical trial for the treatment of 134 patients with genotype 2 who were treated with sofosbuvir plus velpatasvir for 12 weeks resulted in a cure rate of 99%.

ASTRAL 3: In the Phase 3 clinical trial of 277 genotype 3 patients the overall cure rate was 95%. Treatment naïve: In the group of patients without cirrhosis the cure rate was 98% (160 of 163 pts); in the group of patients with cirrhosis the cure rate was 93% (40 of 43 pts). Treatment-experienced: in patients without cirrhosis the cure rate was 91% (31 of 34 pts); in patients with cirrhosis the cure rate was 89% (33 of 37 pts).

The ASTRAL 2 and 3 studies had comparator arms that included 132 genotype 2 patients and 275 patients genotype 3 patients who received sofosbuvir plus ribavirin. The patients who received sofosbuvir plus velapatasvir had higher cure rates and less side effects.

The most common side effects in sofosbuvir plus velpatasvir groups were fatigue, headache, nausea and insomnia.